Synthesis of [closo-B12(OH)11NH3]-: A New Heterobifunctional Dodecaborane Scaffold for Drug Delivery Applications.
- Resource Type
- Article
- Authors
- Bondarev, Oleg; Khan, Aslam A.; Xiaoyan Tu; Sevryugina, Yulia V.; Jalisatgi, Satish S.; Hawthorne, M. Frederick
- Source
- Journal of the American Chemical Society. 9/4/2013, Vol. 135 Issue 35, p13204-13211. 8p.
- Subject
- *CHEMICAL research
*DRUG delivery devices
*DRUG delivery systems
*HYDROGEN peroxide
*CHEMICAL reactions
*FLUORESCENCE microscopy
*PHARMACEUTICAL technology
*HYDROXYLATION
- Language
- ISSN
- 0002-7863
Effective utilization of [closo-B12H12]2- derivatives in targeted drug delivery applications depends upon an efficient strategy to differentiate at least one of the 12 vertices on the B122- core. Precursor molecules must also be able to withstand the initial harsh hydrogen peroxide treatment necessary for hydroxylation of the B-H vertices. We report here a method for preparation of the ammonio derivative [closo-B12(OH)11NH3]- and also demonstrate its utility in construction of a targeted drug delivery scaffold. Treatment of the precursor [closo-B12H11NH3]- with hydrogen peroxide gives the corresponding nitro derivative [closo-B12(OH)11NO2]2- in good yield. The nitro group is easily reduced with hydrogen over a Raney nickel catalyst to produce [closo-B12(OH)11NH3]-. The 11 hydroxyl groups can then be readily converted to carbonates or carbamates. As a proof-of-principle of its utility as a drug delivery system, we used the resulting vertex-differentiated ammonio derivative to construct a platinated pro-drug possessing 11 copies of a carboplatin analogue conjugated to the B122- core via carbamate linkage and a fluorescein molecule attached at the remaining vertex by an amide linkage. In vitro cytotoxicity assays demonstrated that activity of an untagged analog was similar to carboplatin against platinum-sensitive A459 cells and higher than carboplatin against platinum-resistant SK-OV-3 cells. Further fluorescence microscopy revealed that the fluorescein-tagged pro-drug localizes to the nuclei of A459 cells. [ABSTRACT FROM AUTHOR]